INTRODUCTION
Anemia often complicates chronic kidney disease (CKD) and leads to various adverse outcomes and reduced quality of life in patients with CKD. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define anemia as hemoglobin (Hb) concentrations of <13.0 g/dl in men and <12.0 g/dl in women.[1] Data from the National Health and Nutrition Examination Survey have shown that the Hb level starts to fall at an estimated glomerular filtration rate (eGFR) of <75 ml/min/1.73 m2 in men and 45 ml/min/1.73 m2 in women.[2] The prevalence of anemia increases below an eGFR of 60 ml/min/1.73 m2 in men and below 45 ml/min/1.73 m2 in women in the general population. The prevalence of anemia is up to 90% in patients on maintenance hemodialysis (CKD 5D).[3] Anemia occurs earlier and is more severe among patients with diabetic kidney disease, elderly, and African–American.[4] Screening for anemia should generally begin at stage 3 of CKD and should become more frequent as the disease progresses.[5]
PATHOPHYSIOLOGY OF ANEMIA IN CKD
Anemia of CKD is usually normochromic, normocytic without leukopenia or thrombocytopenia. Both life span and red blood cells (RBC) production are reduced. The cause of renal anemia is usually multifactorial, the most important being the absolute or relative deficiency of erythropoietin (EPO). This deficiency may be absolute due to inadequate production of EPO by the failing kidneys or relative due to resistance of target tissues resulting from chronic inflammation and uremia.[4] The second most important cause or contributor is iron deficiency which is much more prevalent in our population. Iron deficiency may be absolute or functional. Hepcidin levels are increased in CKD due to reduced renal clearance and increased inflammatory cytokine.[6] Increased hepcidin enhances iron sequestration and also hinders iron absorption from the gut. Other important causes are bleeding diathesis, iron deficiency due to poor dietary iron absorption and gastrointestinal blood loss, hyperparathyroidism leading to bone marrow fibrosis, folate or Vitamin B-12 deficiency, hemoglobinopathies, chronic inflammation, and comorbid conditions such as hypothyroidism, hyperthyroidism, pregnancy, HIV-associated disease, autoimmune diseases, and use of immunosuppressive drugs. Secondary hyperparathyroidism results in diminished responsiveness to EPO, while uremic toxins and chronic inflammatory milieu result in shortened red cell survival and reduced erythropoiesis.
CLINICAL MANIFESTATIONS
Early diagnosis of anemia is important as even modest anemia is an independent risk factor for hospitalizations, cardiovascular disease (CVD), and mortality.[7] Most of the symptoms previously attributed to the “uremic syndrome” are actually caused by severe anemia associated with CKD. Clinical manifestations include fatigue, decreased exercise tolerance, angina, heart failure, and impaired host defense against infections [Table 1].
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Table 1: Symptoms and signs of anemia
DIAGNOSIS
The evaluation of anemia in CKD patients should include a complete blood count with RBC indices, white blood cell count (including differential), and platelet count. Hb concentration is a better marker of anemia than hematocrit. Although anemia of CKD is typically normochromic and normocytic, macrocytosis may be seen due to deficiency of vitamin B12 or folate, microcytic morphology may be present due to concurrent iron deficiency or inherited disorders of Hb formation (such as thalassemia), or dimorphic presentation due to deficiency of both iron and folate or vitamin B12. Iron profiles including serum iron, TIBC, ferritin, vitamin B12, and folate should be assessed to estimate the level of iron level in blood and tissue stores. Usually, serum ferritin and transferrin saturation (TSAT) are decreased in iron deficiency anemia, but may be raised in CKD due to chronic inflammatory state and thus needs to be interpreted with caution. However, in clinical practice, TSAT remains the most commonly used parameter [Table 2].
Table 2: Laboratory evaluation of anemia
MANAGEMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE
Improvement in quality of life, favorable effects on cardiovascular function, and slowing of renal disease progression are seen with increasing Hb concentrations. This led to an opinion of a Hb level above 10–11 g/dl in all CKD patients.[7,8] They recommend avoiding target Hb level above 13 g/dl as a higher Hb target has been linked to increased risks of thromboembolic events, vascular access thrombosis, strokes, and no survival benefit. This may be due to increased viscosity of blood or may be due to higher doses used to achieve a higher Hb target.[1,4,7,8,9,10]
The beneficial effects of anemia correction on the cardiovascular system are reduction of cardiac output, reduced stroke volume and heart rate leading to a reduction in angina episodes, and myocardial ischemia. It also leads to the regression of left ventricular hypertrophy and stabilization of left ventricular dilation.[9,10] Other favorable effects include reduced blood transfusions, increased exercise capacity, improved immune function, and improved central nervous system symptoms such as cognitive functions, depression, and sleep patterns.[4]
THERAPEUTIC MANAGEMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE
Secondary causes of anemia must be excluded beforehand. EPO-stimulating agents (ESAs) and iron supplementation are the cornerstone treatments. Iron deficiency, if any, should be corrected before starting ESA.
ORAL OR INTRAVENOUS IRON SUPPLEMENT
Oral iron therapy is usually ineffective for CKD 5D patients and only modestly effective CKD 3–5 except for one iron phosphate binder ferric citrate, which is highly efficacious as iron supplement in both populations.[4]
In contrast to oral forms of iron, intravenous (IV) iron is generally highly efficacious. IV iron preparations include iron sucrose, iron dextran, ferric gluconate, ferumoxytol, ferric carboxymaltose, and iron isomaltoside. The major difference is that a larger amount of iron can be administered at a single administration with ferumoxytol, ferric carboxymaltose, and iron isomaltoside compared with iron sucrose and ferric gluconate. Whenever IV iron is used, complications such as hypotension or hypersensitivity should be monitored. IV iron should not be administered during acute infections, as it can make iron available to bacteria and other microorganisms.[4]
ERYTHROPOIESIS-STIMULATING AGENTS[1,4,5,8,9]
- Epoetin alfa and beta – It is a first-generation ESA manufactured by gene transfer into a suitable mammalian cell line such as Chinese hamster ovary (CHO) cells. The ESAs are administered either intravenously or subcutaneously. Although the bioavailability of subcutaneous (SC) ESA is 20%–30%, the prolonged half-life after SC administration compared with IV administration allows less frequent injections. Moreover, the dose required to achieve the same Hb level is almost 30% lower with SC than with IV administration[1,4,5,8]
- Darbepoetin alpha – It is a second-generation ESA. It is a super-sialylated analog of EPO, containing two extra N-linked glycosylation chains. The elimination half-life after single IV administration is 25.3 h (8.5 h for EPO). Darbepoetin can be given once weekly or fortnightly[4,5,8]
- Methoxy polyethylene glycol–epoetin beta (C.E.R.A.) – It is a PEGylated derivative of epoetin beta. Half-life of C.E.R.A is around 130 h. This can be given once fortnightly or monthly
- Peginesatide (Hematide) – It is an EPO-mimetic peptide. It had to be withdrawn from the market due to severe hypersensitivity reactions, including fatal anaphylactic events.
If the serum ferritin concentration is below 100 ng/ml, iron store should be replenished first preferably with IV Iron. Ferric carboxymaltose is the latest parenteral iron that has benefits of both iron dextran and iron sucrose. Recommended serum ferritin level is 100-500 μg/l in CKD non-dialysis patients while 200-500 μg/l in dialysis-dependent patients.[1]
HYPOXIA-INDUCIBLE TRANSCRIPTION FACTOR STABILIZERS: AN EMERGING ORAL THERAPY FOR THE MANAGEMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE
It is also referred to prolyl hydroxylase domain protein inhibitors. It is a competitive inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases and asparaginyl hydroxylase enzymes. Under normal oxygen concentrations, HIF-2 is continuously formed and degraded by prolyl hydroxylase. However, in hypoxic conditions, these enzymes get inhibited, and there is an increased transcription of EPO and iron transporters such as DMT1, DCYTB, and transferrin. It leads to an increase in endogenous EPO production from both the liver and also from the poorly functioning kidneys.[4,5,10,11] These are orally active and increase Hb in a dose-dependent manner. Many of these drugs (e.g. roxadustat, desidustat, daprodustat, vadadustat, and molidustat) are in phase II and III clinical trials.[12,13,14] Roxadustat has been recently approved by FDA. Desidustat is available in the Indian market for use in these patients. Recently, encouraging results are being reported.[12,13,14,15,16]
RED BLOOD CELL TRANSFUSIONS IN CHRONIC KIDNEY DISEASE
Red cell transfusion should be avoided, when possible, in a patient with CKD, especially if he is eligible for organ transplantation to avoid the risk of allosensitization. However, in certain acute clinical situations, patients are transfused when the benefits of red cell transfusions outweigh the risks. This includes when rapid correction of anemia is required to stabilize the patient's condition (e.g. acute hemorrhage and unstable coronary artery disease) and when rapid preoperative Hb correction is required.[1]
EFFECT OF KIDNEY REPLACEMENT THERAPY ON ANEMIA
Adequate hemodialysis in CKD 5D patients usually improves anemia by controlling uremia. Successful kidney transplantation regains normal iron homeostasis and correction of anemia in the majority of patients.
POSTTRANSPLANT ANEMIA
Most of the patients undergoing kidney transplants remain anemic. Although kidney transplantation improves anemia, 30%–40% of kidney transplant recipients (KTR) remain anemic.[17] Posttransplant anemia (PTA) is divided arbitrarily as early occurring within 6 months of transplant and late that occurs 6 months' posttransplant as etiologies in these two types usually differ. Iron deficiency, inadequate iron stores at the time of transplant, blood loss during surgery, and ESA resistance are the most common attributes of early PTA. Risk factors for post-transplant anemia are reduced graft function, graft rejections, infections, and drugs like anti-thymocyte globulins, antimetabolites, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), calcineurin inhibitors, sirolimus, trimethoprim-sulfamethoxazole.[7] PTA is strongly associated with CVD morbidity and mortality in KTR. Diagnosis and management of anemia are similar to that in CKD 3-5 patients with a target Hb 12–13 g/dL. KTRs are usually responsive to IV iron and ESAs.[17,18]
CONCLUSION
Anemia in CKD is a common complication that is treatable. Anemia is significantly and causally associated with increased CVD morbidity and mortality, and a decline in eGFR. Early diagnosis and management are of paramount importance to avoid the ill effects of anemia on renal function and CVD. The management of anemia requires a holistic approach due to its multifactorial pathophysiology. ESAs and iron supplementations are the cornerstones of the management of anemia in CKD. Newer drugs like HIF inhibitors are safe and as effective as ESAs. Anemia in KTR can also be managed with IV or oral iron and ESAs apart from addressing the specific etiologies.
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Conflicts of interest
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REFERENCES
1. KDIGO Anemia Guideline Work Group. . KDIGO clinical practice guideline for anemia in chronic kidney disease Kidney Int Suppl. 2012;2:279–335
2. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: The Third National Health and Nutrition Examination Survey (1988-1994) Arch Intern Med. 2002;162:1401–8
3. McFarlane SI, Chen SC, Whaley-Connell AT, Sowers JR, Vassalotti JA, Salifu MO, et al Prevalence and associations of anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004 Am J Kidney Dis. 2008;51:S46–55
4. Fishbane S, Spinowitz B. Update on anemia in ESRD and earlier stages of CKD: Core curriculum 2018 Am J Kidney Dis. 2018;71:423–35
5. Li ZL, Tu Y, Liu BC. Treatment of renal anemia with roxadustat: Advantages and achievement Kidney Dis (Basel). 2020;6:65–73
6. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization Science. 2004;306:2090–3
7. KDOQI; National Kidney Foundation. . KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease Am J Kidney Dis. 2006;47:S11–145
8. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, et al Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Am J Kidney Dis. 2004;44:94–111
9. Portolés J, Martín L, Broseta JJ, Cases A. Anemia in chronic kidney disease: From pathophysiology and current treatments, to future agents Front Med (Lausanne). 2021;8:642296.
10. Nangaku M, Eckardt KU. Pathogenesis of renal anemia Semin Nephrol. 2006;26:261–8
11. Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond Nat Rev Nephrol. 2016;12:157–68
12. Coyne DW, Goldsmith D, Macdougall IC. New options for the anemia of chronic kidney disease Kidney Int Suppl (2011). 2017;7:157–63
13. Kuriyama S, Maruyama Y, Honda H. A new insight into the treatment of renal anemia with HIF stabilizer Ren Replace Ther. 2020;6:63.
14. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, et al Roxadustat treatment for anemia in patients undergoing long-term dialysis N Engl J Med. 2019;381:1011–22
15. Haase VH. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease Kidney Int Suppl (2011). 2021;11:8–25
16. Wish JB. Hypoxia-inducible factor-prolyl hydroxylase inhibitors for the treatment of anemia in CKD: Additional pieces of the jigsaw puzzle Kidney Int Rep. 2021;6:1751–4
17. Yabu JM, Winkelmayer WC. Posttransplantation anemia: Mechanisms and management Clin J Am Soc Nephrol. 2011;6:1794–801
18. Gafter-Gvili A, Gafter U. Posttransplantation anemia in kidney transplant recipients Acta Haematol. 2019;142:37–43
